title: GRL-04810 and GRL-05010, difluoride-containing nonpeptidic HIV-1 protease inhibitors (PIs) that inhibit the replication of multi-PI-resistant HIV-1 in vitro and possess favorable lipophilicity that may allow blood-brain barrier penetration.
abstract: We designed, synthesized, and identified two novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-04810 and GRL-05010, containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, bis-tetrahydrofuranylurethane (bis-THF), and a difluoride moiety, both of which are active against the laboratory strain HIV-1LAI (50% effective concentrations [EC50s], 0.0008 and 0.003 μM, respectively) with minimal cytotoxicity (50% cytotoxic concentrations [CC50s], 17.5 and 37.0 μM, respectively, in CD4(+) MT-2 cells). The two compounds were active against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to various antiviral regimens. GRL-04810 and GRL-05010 also blocked the infectivity and replication of each of the HIV-1NL4-3 variants selected by up to 5 μM lopinavir (EC50s, 0.03 and 0.03 μM, respectively) and atazanavir (EC50s, 0.02 and 0.04 μM, respectively). Moreover, they were active against darunavir (DRV)-resistant variants (EC50 in 0.03 to 0.034 μM range for GRL-04810 and 0.026 to 0.043 μM for GRL-05010), while DRV had EC50s between 0.02 and 0.174 μM. GRL-04810 had a favorable lipophilicity profile as determined with the partition (log P) and distribution (log D) coefficients of -0.14 and -0.29, respectively. The in vitro blood-brain barrier (BBB) permeability assay revealed that GRL-04810 and GRL-05010 may have a greater advantage in terms of crossing the BBB than the currently available PIs, with apparent penetration indexes of 47.8 × 10(-6) and 61.8 × 10(-6) cm/s, respectively. The present data demonstrate that GRL-04810 and GRL-05010 exert efficient activity against a wide spectrum of HIV-1 variants in vitro and suggest that two fluorine atoms added to their bis-THF moieties may well enhance their penetration across the BBB.
authors.affiliation: Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Pedro Miguel
authors.initials: PM
authors.lastname: Salcedo Gómez
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Sofiya
authors.initials: S
authors.lastname: Yashchuk
authors.forename: Akira
authors.initials: A
authors.lastname: Mizuno
authors.forename: Debananda
authors.initials: D
authors.lastname: Das
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000069446:Atazanavir Sulfate; D001812:Blood-Brain Barrier / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D000069454:Darunavir; D024921:Drug Resistance, Multiple, Viral; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005459:Fluorides / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D000882:Haplorhini; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061466:Lopinavir / Q000494:pharmacology; D008954:Models, Biological; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000494:pharmacology; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D019258:Saquinavir / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D002219:Carbamates; C000593710:GRL-04810; C000593711:GRL-05010; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019258:Saquinavir; D005459:Fluorides; D000069454:Darunavir